Fumagillins are a class of compounds naturally secreted from aspergillus fumigatus fungus. Synthetic analogues of fumagillins provide a class of angiogenesis inhibitors that exhibit potent anti-angiogenic activity and low systemic toxicity. A synthetic derivative of fumagillin having a formula (I): ##STR1##
has been described in European Patent No. 0 359 036 and European Patent No. 0 357 061 as having inhibitory effect of suppressing the proliferation of endothelial cells and inhibiting neovascularization. The compounds having angiogenesis inhibiting activity have use in treating tumors in cancerous conditions. (Cancer Medicine, 3d. edition, Lea & Febiger, Philadelphia (1993)).
Developing stable formulations for delivering effective amounts of medicament to target organs presents unique challenges in obtaining a suitable formulation for the medicament. Characterized by their lipophilic properties and low water solubility, these drugs typically result in formulations producing low oral bioavailability. European Patent No. 0 602 586 discloses a pharmaceutical composition comprising a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin. Typical formulations are less effective for delivery of the medicament to the angiogenic tumors due to low oral bioavailability of the medicament in the formulation.
Recent developments in drug formulation have resulted in self-emulsifying drug systems (SES) being used as vehicles for orally administering lipophilic medicaments. (Charman, Pharmaceutical Research, 39(1): 87-93 (1992)). Self-emulsifying systems are generally recognized to be mixtures of oil and surfactant which, upon exposure to aqueous media, form isotropic dispersions stabilized by an interfacial film of surfactant molecules.
Several self-emulsifying systems containing active drug in mixtures of oil and surfactant, which emulsify and form dispersions under gentle agitation, have been described using various components and for numerous uses.
European Patent No. 0 517 412 describes an oil-based self-emulsifying formulation containing benzodiazepine compounds useful for treating pain, panic, or anxiety.
The self-emulsifying systems described in Shah, Intl. J. of Pharm., 106:15-23 (1994) contain polyglycolized glyceride oils with varying fatty acid and polyethylene glycol.
Pouton, et al., Intl. J. of Pharm., 27:335-348 (1985), discloses self-emulsifying systems containing Miglyol 812 or Miglyol 840 oils in combination with Tween 85 surfactant.
Pharmaceutical formulations wherein the composition is in the form of a self-emulsifying system have particularly advantageous properties with respect to the above fumagillol derivative. Formulations of fumagillin anticancer agents in typical self-emulsifying systems rapidly degrade if formulated without a suitable stabilizing component. Therefore, there continues to be a need to provide effective methods of formulating fumagillin anticancer agents to ensure more effective bioavailability and wider availability of the desired medicaments.